Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the United States. This condition encompasses both hepatic steatosis and the more severe non-alcoholic steatohepatitis. It is now estimated that 14-24% of the general population and up to 80% of morbidly obese subjects have contracted NAFLD. Untreated disease may progress to cirrhosis and lead to hepatic cancer. Cirrhosis now accounts for 12.5% of diabetes related deaths. In spite of the recognized need and degree of interest in the literature, there are no currently approved therapeutic agents for treatment of NAFLD and this unmet medical need will likely continue to increase in concert with the epidemic of obesity. The overall objective of the proposed research is to discover a PPAR?-sparing thiazolidinedione (TZD) which displays efficacy in a rodent model of non-alcoholic fatty liver disease (NAFLD) and demonstrates the necessary drug-like qualities to become a potential clinical candidate for human therapeutics. The TZD class of insulin sensitizing agents are conventionally thought to operate through binding to PPAR? receptors. However, it is the strong contention of the authors of this proposal that the undesirable effects of the TZDs are mediated by binding to PPAR? receptors. Moreover, it has recently been suggested that rosiglitazone, the prototypical PPAR? activator, could exert untoward acute cardiovascular effects. Contrary to the prevailing scientific view, the authors of this proposal believe that non-PPAR mediated mechanisms are responsible for the insulin sensitizing pharmacology. The co-founders of the Metabolic Solutions Development Company (MSDC) have conceived of TZDs which should display minimal or no binding to the PPAR? receptor and has extensively evaluated their activity in cellular models (brown adipose precursor cell differentiation) and in rodent models of Type 2 diabetes. In Phase I studies, we evaluated a PPAR-sparing analog on a rodent model of NAFLD and the results clearly show that it improves insulin sensitivity accompanied by increased ability of the liver to oxidize and clear fat. Thus, the positive completion of this project provides an excellent foundation for selecting and developing a PPAR?- sparing TZD for treatment of NAFLD devoid of the side effects typically associated with this class of medications. The experimental work planned for Phase II would build on and extend this technology to achieve the selection and initial preclinical development of an analog for treatment of NAFLD as well as the potential identification of a biomarker which could be useful for detection of early disease and to monitor therapeutic progress in clinical trials. PUBLIC HEALTH RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the U.S. and the incidence of this disease has risen concomitantly with the epidemic of obesity. There is currently no approved therapeutic treatment for this liver disease. It is the overall goal of the proposed research to identify a candidate drug from the thiazolidinedione class which can be submitted to a development program for therapeutic use in treatment of NAFLD.